2016-11-01 14:07:08

Prelude

Prelude

Today's Topics

  • Disorder and disease
    • Affective disorders

Framework

  • Symptoms
  • Genetic risk
  • Neurological factors
  • Neurochemical factors

The face of depression

The face of depression

Major affective (emotional) disorders

  • Types
    • Anxiety
    • Depression
    • Bipolar disorder

Major affective (emotional) disorders

  • Heritability
    • proportion of variance in trait accounted for by genetic factors
    • Monozygotic: .69
    • Dizygotic: .13

Depression

  • Symptoms
    • Insomnia, lethargy, loss of pleasure, interest, energy
  • Agitation
  • Lasting for several weeks or more
  • Prevalence (~16% lifetime)
  • Females 2-3x males

Cognitive model

…negative cognitive biases in depression are facilitated by increased influence from subcortical emotion processing regions combined with attenuated top-down cognitive control.

(Disner et al. 2011)

(Disner et al. 2011)

(Disner et al. 2011)

(Disner et al. 2011)

Neurological factors

(Videbech and Ravnkilde 2004)

(Videbech and Ravnkilde 2004)

Neurological factors

(Fitzgerald et al. 2008)

  1. patients v. controls, (b) patients on SSRIs, (c) patients v. ctrls (happy stim), (d) patients v. controls (sad stim)

Neurological Factors

  • Persistent activation in amygdala
  • Amygdala and dorsolateral prefrontal cortex (DLPFC) inversely related
  • (Siegle et al. 2002)

(Siegle et al. 2002)

(Siegle et al. 2002)

Disrupted connectivity

  • Resting state fMRI (rsFMRI) in 421 patients with major depressive disorder and 488 control subjects.
  • Reduced connectivity between orbitofrontal cortex (OFC) and other areas of the brain
  • Increased connectivity between lateral PFC and other brain areas

(Cheng et al. 2016)

Disturbed sleep

Pharmacological factors

  • Lowered thyroid function
  • High/chronic cortisol levels
  • Monoamine hypothesis, (Schildkraut 1965)
    • More: euphoria
    • Less: depression
    • Resperine (antagonist for NE & 5-HT) can cause depression

Pharmacological factors

  • Serotonin hypothesis, (Coppen 1967).

(Samuelsson et al. 2006)

Treatments for depression

"First generation" drugs

  • Monoamine oxidase (MAO) inhibitors (MAO-Is)
    • MAO destroys excess monoamines in terminal buttons
    • MAO-I’s boost monoamine levels
    • side effects may include "serotonin syndrome"
      • Agitation or restlessness, + HR/resp/temp/BP, diarrhea/nausea/vomiting, loss of coordination

"First generation" drugs

  • Tricyclics
    • Inhibit NE, 5-HT reuptake
    • Upregulate monoamine levels
      • inhibit SERT and NET
    • but non-selective = side effects
      • BP/HR, dry mouth, constipation, drowsiness, anxiety
      • antagonists for 5-HT, NE, NMDA, histamine, and ACh receptors

"Second and third generation" drugs

  • Selective Serotonin Reuptake Inhibitors (SSRIs)
    • Block action of 5-HT transporter (SERT)
    • Fluoxetine (Prozac, Paxil, Zoloft)
    • Prolong duration 5-HT in synaptic cleft
    • Also increase brain steroid production

Others

  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
    • e.g., Cymbalta, Effexor
  • Norepinephrine reuptake inhibitors (NRI, NERI) or adrenergic reuptake inhibitors (ARI)
  • Norepinephrine-Dopamine Reuptake Inhbitors (NDRIs)
    • e.g., Wellbutrin

How well do the drugs work?

  • STAR*D trial
  • On SSRI for 12-14 weeks. ~1/3 achieved remission; 10-15% showed symptom reduction.
  • If SSRI didn't work, could switch drugs. ~25% became symptom free.
  • 16% of participants dropped out due to tolerability issues
  • Took 6-7 weeks to show response.

Who will benefit from drug therapy?

  • Depends on
    • Early life stress
    • Brain (amygdala) response to emotional faces
  • (Goldstein-Piekarski et al. 2016)
  • Low-stress + low amyg reactivity -> > responding
  • High stress + high amyg reactivity -> > responding

Revisiting the serotonin hypothesis

Problems with monoamine/5-HT hypothesis

  • Too simplistic
  • NE, 5-HT interact
  • Drugs fast acting (min), but improvement slow (weeks)

What do drugs do, then?

  • Receptor sensitivity altered?
    • Presynaptic serotonin autoreceptors compensate
    • Postsynaptic upregulation of NE/5-HT effects
    • Link to neurotrophin BDNF, (Duman and Monteggia 2006)
    • BDNF boosts neurogenesis

Exercise as a treatment

Drugs vs. therapy

(DeRubeis, Siegle, and Hollon 2008)

(DeRubeis, Siegle, and Hollon 2008)

(DeRubeis, Siegle, and Hollon 2008)

Electroconvulsive Therapy (ECT)

  • Last line of treatment for drug-resistant depression
  • Remission rates of up to 50.9% (Dierckx et al. 2012)
  • Seems to work via
    • Anticonvulsant (block Na+ channel or enhance GABA function) effects
    • Neurotrophic (stimulates neurogenesis) effects

Neurogenesis hypothesis, (Mahar et al. 2014)

  • Chronic stress causes neural loss in hipp
  • Chronic stress downregulates 5-HT sensitivity
  • Depression ~ chronic stress
  • Anti-depressants may upregulate neurogenesis via 5-HT modulation

Depression's widespread impact

  • Widespread brain dysfunction
  • Prefrontal cortex, amygdala, HPA axis, circadian rhythms
  • Genetic + environmental factors
  • Disturbance in 5-HT, NE systems, cortisol

Bipolar disorder

The face of bipolar disorder

Bipolar disorder

  • Formerly “manic depression” or “manic depressive disorder
  • Alternating mood states
    • Mania or hypomania (milder form)
    • Depression
  • Cycles 3-6 mos in length, but
    • Rapid cycling (weeks or days)
  • Suicide risk 20-60x normal population, (Baldessarini, Pompili, and Tondo 2006)

Symptoms

Prevalence, subtypes

  • 1-3% prevalence
  • Subtypes
    • Bipolar I: manic episodes, possible depressive ones
    • Bipolar II: no manic episodes but hypomania + depression

Genetics

  • Overlap between bipolar disorder and schizophrenia
  • Genes for voltage-gated Ca++ channels
    • Regulate NT, hormone release, NMDA receptor effects
    • Gene expression, cell metabolism
  • (Craddock and Sklar 2013)

Brain responses to emotional faces ≠ depression

(Lawrence et al. 2004)

(Lawrence et al. 2004)

Amyg, Hip volume reduced,

(Hallahan et al. 2011)

Drug treatments

  • Mood stabilizers
    • Lithium (Li)
    • Valproate
  • Anticonvulsants
    • GABA agonists
    • Usually to treat epilepsy
    • e.g. lamotrigine (Lamictal)
  • Antipsychotics

Effects of Lithium

  • Reduces mania, minimal effects on depressive states
  • Increases/preserves PFC, hip, amyg volume
  • downregulates DA, glu; upregulates GABA
  • modulates 5-HT, NE
  • (Malhi et al. 2013)

What does lithium do?

At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission…

(Malhi et al. 2013)

An Unquiet Mind

BP summed-up

  • Changes in mood, but ≠ depression
  • Genetic + environmental risk
  • Changes in emotion processing network activity, size of hippocampus
  • But, heterogeneous
  • No simple link to a specific NT system

Postlude

References

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Schildkraut, Jj. 1965. “The Catecholamine Hypothesis of Affective-Disorders - a Review of Supporting Evidence.” American Journal of Psychiatry 122 (5): 509–22.

Siegle, Greg J., Stuart R. Steinhauer, Michael E. Thase, V. Andrew Stenger, and Cameron S. Carter. 2002. “Can’t Shake That Feeling: Event-Related fMRI Assessment of Sustained Amygdala Activity in Response to Emotional Information in Depressed Individuals.” Biological Psychiatry 51 (9): 693–707. doi:10.1016/S0006-3223(02)01314-8.

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